Diabetes is at epidemic proportions with 300 million people projected to have diabetes by 2025. Heart disease is the cause of death in 80% of diabetic patients of which the major contributing factor is coronary artery disease. Diabetics suffer from a diabetic cardiomyopathy independent of the vascular effects of hypertension or coronary artery disease. This suggests that there are contributing factors within the cardiac myocyte itself that may give rise to detrimental cardiac remodeling associated with diabetes. Diabetic cardiomyopathy is triggered by alteration in fatty acid metabolism, hyperinsulinemia, and hyperglycemia. Diabetic cardiomyopathy involves complex changes in signaling and metabolism that may be regulated at multiple levels: 1) altered cellular signaling through differential regulation of receptor/effector expression and localization; 2) altered mitochondrial function and dynamics; 3) altered nuclear activity leading t pathologic gene expression that may ultimately affect the latter two factors. As such, membrane/cytoplasmic signaling, mitochondria, and the nucleus could be defined as three control points that limit the ability of the heart to adapt to diabetic stress and offer novel therapeutic targets. A common molecular regulator at these three sites has not been identified. An emerging idea in signal transduction suggests signaling molecules exist as dynamic, spatially organized multi-protein complexes in lipid-rich microdomains of the plasma membrane continuously forming and dissociating under basal or stimulated conditions. Caveolae are cholesterol and sphingolipid-enriched microenvironments that form microscopically distinct flask-like invaginations of the plasma membrane. Our novel preliminary data show that heart-specific caveolin-3 overexpression (Cav-3 OE) protects hearts from diabetic cardiomyopathy in a model of Type II diabetes by modulating function of membrane/cytoplasmic signaling, mitochondria, and the nucleus. We hypothesize that the localized expression and regulatory activity of caveolin in the membrane/cytoplasm, mitochondria, and/or the nucleus are critical to protection of the heart from diabetic cardiomyopathy. Targeted expression of caveolin may provide a detailed understanding of the molecular role of caveolin in diabetes to provide more directed targeting of therapeutics. The following aims are proposed: Aim 1: Determine the role of caveolin in membrane/cytoplasmic signaling and the therapeutic potential of membrane-targeted caveolin expression in the progression of diabetic cardiomyopathy. Aim 2: Determine the role of caveolin in mitochondrial function and dynamics and the therapeutic potential of mitochondrial-targeted caveolin expression in the progression of diabetic cardiomyopathy. Aim 3: Determine the role of caveolin in nuclear envelope stability, modulation of gene expression, and the therapeutic potential of nuclear-targeted caveolin expression in the progression of diabetic cardiomyopathy.